Free Energy Study on HBD-3 Translocation on Lipid Membrane

Abstract

Human defensins are a class of antimicrobial peptides that are crucial components of the innate immune system. Human β defensin type 3 (hBD-3) has been discovered recently, and has a charge density of +11. It includes 3 pairs of intramolecular disulfide bonds, which can break and converts hBD-3 into the linear analog form under reducing conditions. hBD-3 can selectively disrupt bacterial lipid membrane, cause cell leakage thus kill the bacterial cell. But the structural basis for the membrane-disrupting function of hBD is still unknown. In order to understand the interaction mechanism of hBD-3 with zwitterionic (but charge-neutral) lipid membrane, umbrella-sampling simulations were performed on the hBD-3 wildtype as well as the linear analog, both in the monomer and dimer forms. Based on the free energy calculation, both hBD-3 wildtype and linear analog need to overcome a very high energy barrier in order to translocate through the neutrally charged lipid bilayer. hBD-3 without disulfides is much more flexible than the wildtype, and thus the hBD-3 analog can pass through the lipid bilayer relatively easier energetically. Furthermore, forming a dimer can also help to decrease the energy barrier significantly. Based on this simple model, forming a higher order oligomer at high concentration is necessary for hBD-3 to transpass the normal cell lipid membrane.